The broad, long term objective of this project is to reduce morbidity and mortality caused by papillary thyroid carcinoma (PTC) which accounts for - 80% of all thyroid cancer. PTC displays remarl<ably high heritability suggesting the existence of genes that when mutated predispose to PTC. The traditional way of searching for such genes is by linkage analysis in families with multiple affected individuals. Despite vigorous world-wide research this approach has yielded modest results in that only 3 genes have been detected that in all lil<elihood cause PTC, and the total number of individuals affected by these genes is minimal. This has led to the hypothesis that the putative culpable genes are either common but of extremely low effect size (penetrance) or might be of higher penetrance but rare or super rare. Our genome wide association studies (GWAS) have begun to sustain this hypothesis in that several loci with low effect size have been detected. We are focusing on rare higher penetrance genes in families in this Project based on findings from the first cycle of this POl. In particular, a novel type of gene, long intergenic noncoding RNA (lincRNAs) appears to underlie at least some of these susceptibility loci. We are presently applying whole genome sequencing to members of affected families in search of further culpable genes. At least one case of an ultra rare high penetrance gene has been detected in this way, and with improvements in technology this avenue likely will lead to a fuller understanding of the genetic predisposition to PTC.